Human immunodeficiency virus (“HIV”) infection and related diseases are a major public health problem worldwide. Human immunodeficiency virus type 1 (“HIV-1”) encodes three enzymes that are required for viral replication: reverse transcriptase, protease, and integrase. Although drugs targeting reverse transcriptase and protease are in wide use and have shown effectiveness, particularly when employed in combination, toxicity and development of resistant strains have limited their usefulness (Palella, et al., N. Engl. J. Med. (1998) 338:853-860; Richman, Nature (2001) 410:995-1001).
A goal of antiretroviral therapy is to achieve viral suppression in an HIV-infected human. Treatment guidelines published by the United States Department of Health and Human Services provide that achievement of viral suppression requires the use of combination therapies, i.e., several drugs from at least two or more drug classes. (PANEL ON ANTIRETROVIRAL GUIDELINES FOR ADULTS AND ADOLESCENTS: GUIDELINES FOR THE USE OF ANTIRETROVIRAL AGENTS IN HIV-1-INFECTED ADULTS AND ADOLESCENTS. Department of Health and Human Services. Available at http://aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Section accessed Apr. 19, 2017.)
A number of reviews of clinical data involving large patient populations have established that a viral load decreases following antiretroviral therapy (“ART”) initiation and that decrease correlates with a reduced risk of AIDS progression or death. (Murray J S, Elashoff M R, Iacono-Connors L C, Cvetkovich T A, Struble K A. The use of plasma HIV RNA as a study endpoint in efficacy trials of antiretroviral drugs. AIDS. 1999;13(7):797-804; Marschner I C, Collier A C, Coombs R W, et al. Use of changes in plasma levels of human immunodeficiency virus type 1 RNA to assess the clinical benefit of antiretroviral therapy. J Infect Dis. 1998; 177(1):40-47; and, Thiebaut R, Morlat P, Jacqmin-Gadda H, et al, with the Groupe d'Epidemiologie du SIDA en Aquitaine (GECSA); Clinical progression of HIV-1 infection according to the viral response during the first year of antiretroviral treatment. AIDS. 2000;14(8):971-978.) In light of these findings, viral load testing may be used as a surrogate marker of a positive treatment response. (Human immunodeficiency virus type 1 RNA level and CD4 count as prognostic markers and surrogate end points: a meta-analysis. HIV Surrogate Marker Collaborative Group. AIDS Res Hum Retroviruses. 2000; 16(12):1123-1133.) A statistically significant change in viral load is a three-fold change, which equates to a 0.5 log10 copies/mL change. Depending on the study or assay used, viral suppression in general is defined as a viral load below the level of detection, which is an HIV RNA copy number of less than 20 to 75 copies/mL. (Damond F, Roquebert B, Benard A, et al. Human immunodeficiency virus type 1 (HIV-1) plasma load discrepancies between the Roche COBAS AMPLICOR HIV-1 MONITOR Version 1.5 and the Roche COBAS AmpliPrep/COBAS TaqMan HIV-1 assays. J Clin Microbiol. 2007; 45(10):3436-3438.)
More than 25 antiretroviral (ARV) drugs in 6 mechanistic classes are Food and Drug Administration (FDA)-approved for treatment of HIV infection. These 6 classes include the nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), a fusion inhibitor (FI), a CCR5 antagonist, and integrase strand transfer inhibitors (INSTIs). In addition, two drugs, ritonavir (RTV or r) and cobicistat (COBI or c) are used solely as pharmacokinetic (PK) enhancers (ie, boosters) to improve the PK profiles of some ARV drugs (e.g., PIs and the INSTI elvitegravir [EVG]).
A standard course of care for a patient infected with HIV is to treat them with a combination of three or more antiviral agents. The initial ARV regimen for a treatment-naive patient generally consists of two different NRTIs, targeting HIV reverse transcriptase (a “backbone”) usually abacavir/larnivudine (ABC/3TC), tenofovir alafenamide/emtricitabine (TAF/FTC), or tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) one or more agents active against one or more different HIV targets, such as an HIV protease inhibitor (“PI”) or an HIV integrase inhibitor. For certain patients infected with HIV or diagnosed with AIDS there is an unmet medical need to two treat them with fewer antiviral agents. There are a number of reasons for giving fewer anti-HIV drugs.
For one, long-term use of certain antiretroviral drugs, particularly nucleoside reverse transcriptase inhibitors can lead to treatment-associated toxicities. Further, historical experience with HIV infected patients shows that many of them are now living longer. This population shows many typical age-related comorbidities, including renal disease, cardiovascular disease, liver disease, cognitive decline, diabetes, dyslipidemia, and osteoporosis, among others. Drug-sparing approaches would be beneficial for this aging population. (McCutchan J A, Wu J W, Robertson K, Koletar S L, Ellis R J, Cohn S, et al. (2007) HIV suppression by HAART preserves cognitive function in advanced, immune-reconstituted AIDS patients. AIDS 21: 1109-1117; Salter M L, Lau B, Go V F, Mehta S H, Kirk G D (2011) HIV infection, immune suppression, and uncontrolled viremia are associated with increased multimorbidity among aging injection drug users. Clin. Infect. Dis. 53: 1256-1264.) These comorbidities can be exacerbated by drug-related adverse events from long-term antiretroviral use. (Cunningham J, Sprague S M, Cannata-Andia J, Coco M, Cohen-Solal M, Fitzpatrick L, et al. (2004) Osteoporosis in chronic kidney disease. Am J Kidney Dis 43: 566-571; Sabin C A, Worm S W, Weber R, Reiss P, El-Sadr W, Dabis F, et al. (2008) Use of nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in HIV-infected patients enrolled in the D:A:D study: a multi-cohort collaboration. Lancet 371: 1417-1426).
These varied problems have led to attempts to try dual antiretovital therapies, but studies have revealed a higher risk of treatment failure compared triple therapy regimens. (Havlir D V, Marschner I C, Hirsch M S, Collier A C, Tebas P, Bassett R L, et al. (1998) Maintenance antiretroviral therapies in HIV infected patients with undetectable plasma HIV RNA after triple-drug therapy. AIDS Clinical Trials Group Study 343 Team. N Engl J Med 339: 1261-1268; Pialoux G, Raffi F, Brun-Vezinet F, Meiffredy V, Flandre P, Gastaut J A, et al. (1998); A randomized trial of three maintenance regimens given after three months of induction therapy with zidovudine, lamivudine, and indinavir in previously untreated HIV-1-infected patients. Trilege (Agence Nationale de Recherches sur le SIDA 072) Study Team. N Engl J Med 339: 1269-1276; Reijers M H, Weverling G J, Jurriaans S, Wit F W, Weigel H M, Ten Kate R W, et al. (1998); Maintenance therapy after quadruple induction therapy in HIV-1 infected individuals: Amsterdam Duration of Antiretroviral Medication (ADAM) study. Lancet 352: 185-190.).
Although different combinations of antiretroviral drugs have been developed for the treatment of HIV and AIDS, a need still exists for additional treatment regimens tailored to patient needs, such as safe and effective two drug antiretroviral regimens.